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Transcriptional elongation requires DNA break-induced signalling

Author

Listed:
  • Heeyoun Bunch

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Brian P. Lawney

    (Center for Cancer Computational Biology, Dana Farber Cancer Institute)

  • Yu-Fen Lin

    (University of Texas Southwestern Medical Center)

  • Aroumougame Asaithamby

    (University of Texas Southwestern Medical Center)

  • Ayesha Murshid

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Yaoyu E. Wang

    (Center for Cancer Computational Biology, Dana Farber Cancer Institute)

  • Benjamin P. C. Chen

    (University of Texas Southwestern Medical Center)

  • Stuart K. Calderwood

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

Abstract

We have previously shown that RNA polymerase II (Pol II) pause release and transcriptional elongation involve phosphorylation of the factor TRIM28 by the DNA damage response (DDR) kinases ATM and DNA-PK. Here we report a significant role for DNA breaks and DDR signalling in the mechanisms of transcriptional elongation in stimulus-inducible genes in humans. Our data show the enrichment of TRIM28 and γH2AX on serum-induced genes and the important function of DNA-PK for Pol II pause release and transcriptional activation-coupled DDR signalling on these genes. γH2AX accumulation decreases when P-TEFb is inhibited, confirming that DDR signalling results from transcriptional elongation. In addition, transcriptional elongation-coupled DDR signalling involves topoisomerase II because inhibiting this enzyme interferes with Pol II pause release and γH2AX accumulation. Our findings propose that DDR signalling is required for effective Pol II pause release and transcriptional elongation through a novel mechanism involving TRIM28, DNA-PK and topoisomerase II.

Suggested Citation

  • Heeyoun Bunch & Brian P. Lawney & Yu-Fen Lin & Aroumougame Asaithamby & Ayesha Murshid & Yaoyu E. Wang & Benjamin P. C. Chen & Stuart K. Calderwood, 2015. "Transcriptional elongation requires DNA break-induced signalling," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10191
    DOI: 10.1038/ncomms10191
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    Cited by:

    1. Heeyoun Bunch & Deukyeong Kim & Masahiro Naganuma & Reiko Nakagawa & Anh Cong & Jaehyeon Jeong & Haruhiko Ehara & Hongha Vu & Jeong Ho Chang & Matthew J. Schellenberg & Shun-ichi Sekine, 2023. "ERK2-topoisomerase II regulatory axis is important for gene activation in immediate early genes," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Rajashree A. Deshpande & Alberto Marin-Gonzalez & Hannah K. Barnes & Phillip R. Woolley & Taekjip Ha & Tanya T. Paull, 2023. "Genome-wide analysis of DNA-PK-bound MRN cleavage products supports a sequential model of DSB repair pathway choice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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